Understanding the Role of Tumor Heterogeneity of Treatment Resistant Prostate Cancer Using Avataroid Technology

About Understanding the Role of Tumor Heterogeneity of Treatment Resistant Prostate Cancer Using Avataroid Technology

Scientists have known that prostate cancer cells are vastly different, or heterogeneous, from one man to another, and even vastly different from one tumor site to another, in the same man. Yet to study prostate cancer, they’ve relied on a very limited number of prostate cancer (PCa) cell lines or animal models that broadly mimic the disease. Thus, to date, pre-clinical work in testing drugs against PCa, or why PCa cells become resistant to a certain drug therapy, had to be done as a sort of group experiment. But researchers were limited by available technology.

The very idea of being able to recreate in the laboratory an exact replica of a man’s prostate tumor that is genetically indistinguishable from his primary tumor or metastatic tumor in his body, once seemed like science-fiction. A holy grail of PCa research is to be able to recreate what can be thought of as avatars for each tumor in each man so that scientists can study the molecular and other interactions that occur inside a tumor, between cancer cells and in the tumor microenvironment. Such an avatar of a man’s unique tumor or tumors would not only allow researchers to study how a particular cancer develops and changes over time, potentially enabling therapies to be developed that would arrest cancer progression, it has the marvelous potential to lessen patient discomfort. Avatar technology would allow testing a drug in the lab to determine how an individual patient is likely to respond without having to subject the patient to drug side effects and toxicities in order to find out.

Dr. Chen and colleagues are taking the fiction out of this science. Using human PCa cells and a specific “miracle-grow” admixture of human growth factors and signaling compounds, they have generated such personalized tumor avatars. Known as “organoids,” or “tumoroids,” Chen et al, have established a highly efficient means of stably growing these cancer avatars in the laboratory. They’ve also shown that these organoids can easily be shipped to other labs—ease of transport would allow patients across the country, or even the world, to benefit from this technology.

Under this Challenge Award, Chen and his team will further develop this technology and investigate how their organoids can aid in making clinical decisions, such as which drug to give a patient and when. Their study will recruit ~10 men per year with treatment-resistant PCa who are about to start therapy with Xtandi or Zytiga or the experimental anti-androgen ARN-509. They will use circulating tumor cells taken from a patient’s blood or cells taken from patient biopsy samples to create organoids for each man, both before he begins treatment and after treatment. They will evaluate how well each man’s pair of organiods corresponds to that man’s clinical response to the drug. They will be able to interrogate the organoid at the molecular level to help elucidate why a man responded to a treatment or did not. This work is essential to bringing organoid technology into clinical use and will help establish the validity/reliability of organoid/tumoroid technology for PCa patients.

What this means for patients: Being able to know what drug will benefit a patient before it is administered or what can be done to prevent resistance to a drug from developing will mean far less suffering for patients and increased longevity. Dr. Chen and his team will prove that avatars—exact replicas of a patient’s tumor—can be routinely used to help doctors make clinical decisions such as what drug is most likely to help a particular patient. Apart from being able to “test first” on a tumor avatar rather than in a patient himself, this work will also greatly aid in novel drug discovery that can be then be targeted to men based upon the unique genetic makeup of their tumor or tumors.

Principal Investigator:

Yu Chen, MD, PhD (Memorial Sloan-Kettering Cancer Center)

Co-investigators:

Howard Scher, MD (MSKCC), James Hicks, PhD (Cold Spring Harbor Laboratory), Binzhi Qian, PhD (MSKCC), Brett Carver, MD (MSKCC), Daniel Danila, MD (MSKCC), Anuradha Gopalan, MD (MSKCC), Stephen Solomon, MD (MSKCC).